chr7-147216448-C-T

Variant names:

• chr7-147216448-C-T
• rs1603450
• NM_014141.6:c.1349-83693C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014141.6(CNTNAP2):​c.1349-83693C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 151,898 control chromosomes in the GnomAD database, including 5,214 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (5214 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.268
• Publications: 4 publications found

Genes affected

CNTNAP2 (HGNC:13830): (contactin associated protein 2) This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, thrombospondin N-terminal-like domains and a putative PDZ binding site. This protein is localized at the juxtaparanodes of myelinated axons, and mediates interactions between neurons and glia during nervous system development and is also involved in localization of potassium channels within differentiating axons. This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome. It is directly bound and regulated by forkhead box protein P2, a transcription factor related to speech and language development. This gene has been implicated in multiple neurodevelopmental disorders, including Gilles de la Tourette syndrome, schizophrenia, epilepsy, autism, ADHD and intellectual disability. [provided by RefSeq, Jul 2017]

CNTNAP2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, NO_KNOWN Submitted by: ClinGen
• cortical dysplasia-focal epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1349-83693C>T		intron_variant	Intron 8 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1349-83693C>T		intron_variant	Intron 8 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1349-83693C>T		intron_variant	Intron 8 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35628 AN: 151778 Hom.: 5206 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.264

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.235 AC: 35658 AN: 151898 Hom.: 5214 Cov.: 32 AF XY: 0.240 AC XY: 17803 AN XY: 74238

African (AFR) AF: 0.266 AC: 11025 AN: 41456

American (AMR) AF: 0.343 AC: 5230 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 707 AN: 3462

East Asian (EAS) AF: 0.715 AC: 3677 AN: 5146

South Asian (SAS) AF: 0.387 AC: 1868 AN: 4826

European-Finnish (FIN) AF: 0.109 AC: 1156 AN: 10576

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10977 AN: 67858

Other (OTH) AF: 0.266 AC: 562 AN: 2112

Alfa AF: 0.192 Hom.: 13570

Bravo AF: 0.254

Asia WGS AF: 0.500 AC: 1735 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.3
DANN	Benign	0.58
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1603450; hg19: chr7-146913540;